Pyrimidine derivatives, including rosuvastatin compounds with a (3R, 5S) configuration, have been recognized for their ability to inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Because HMG-CoA reductase plays a major role in the synthesis of cholesterol, these pyrimidine derivatives have been described as useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis (U.S. Pat. RE 37,314). A number of other compounds have similarly been described as useful in the inhibition of HMG-CoA reductase, and thus in the treatment of atherosclerosis, including pravastatin sodium (U.S. Pat. No. 4,346,227), simvastatin (U.S. Pat. No. 4,444,784), and certain mevalonate and mevalonolactone derivatives (U.S. Pat. No. 5,849,777).
Compounds in this latter category (mevalonate and mevalonolactone derivatives) have also been recognized for their ability to modulate cell function. See U.S. Pat. No. 5,849,777, which is hereby incorporated by reference. Because abnormal cell function is associated with a number of diseases, including cancer and Acquired Immune Deficiency Syndrome (AIDS), the ability to enhance or modulate cell function is therefore of significant importance in the treatment of diseases associated with such aberrant or deficient cell function. Unfortunately, despite research efforts spanning a number of decades, modulation of cellular activity, including differentiation, is still incompletely understood, partly a result of the numerous and complex pathways by which such modulation occurs. The mevalonate and mevalonolactone derivates described in U.S. Pat. No. 5,849,777 are believed to function by modulating phenotypic expression, such as by inducing expression of unexpressed genes so as to increase cell function, and/or by normalizing cell surface membrane characteristics including the expression of oligosaccharides.
Although some compounds that inhibit HMG-CoA reductase are also useful as cell modulators, there is no apparent correlation between the inhibition of HMG-CoA reductase and cell modulation. In addition, the relevant literature has recognized the importance of distinguishing between enantiomeric forms of pharmaceutically active substances due to potential differences in pharmacologic activity as well as the difficulty in predicting the therapeutically relevant characteristics of any given enantiomeric form (Darrow, J., The Patentability of Enantiomers, Implications for the Pharmaceutical Industry, Stanford Technology Law Review, 2007, pages 2 et seq.).